The FDA and NCI co-sponsored a public workshop on the NIH campus in December 1998, with the goal of exchanging information about characterization of tumor vaccines and clinical end-points for vaccine studies. Issues discussed included: regulatory considerations in tumor vaccines; phenotypic and functional characterization of dendritic cells, or other antigen-presenting cells; autologous and allogeneic tumor cells as tumor vaccines; preclinical strategies; immunological assessment in early clinical trials; and detection of tumor cells in cellular vaccines. In the regulatory session, FDA speakers emphasized that, although tumor vaccines may be challenging to study, safety and efficacy were still of fundamental importance. In preparation of a vaccine trial, preclinical studies were expected to: provide data for the initial dose and dose schedule; identify potential target organs for toxicity; identify laboratory correlates for monitoring; and determine the mechanism of action of the vaccine. Safety issues included: injection-site reactions; induction of autoimmunity and lymphadenopathy; hypersensitivity; pyrogenicity; dysregulation of cytokines; and induction of disease. In the discussion of trial design, it was recognized that the assessment of tumor vaccines might well deviate from the standard approach used for cancer chemotherapeutics, especially given the minimal acute toxicity of these agents. Potential alternative designs included: Phase I studies, with large patient cohorts, large intervals between dose levels and the use of the optimal biologic dose (OBD)) rather than the maximal tolerated dose (MTD); randomized Phase II studies with contemporaneous controls, especially for studies of combinations of biologics; and clinical surrogate end-points for Phase III studies. However, laboratory correlates were not considered an acceptable end-point, especially for Phase III studies, unless validated to predict for clinical outcome. The biology of antigen-presenting cells was reviewed in detail. Regulatory aspects addressed included: identity and potency testing; elimination of contaminating cells; functional assays; and antigen characterization. A request was made to develop a consensus, on at least identity, that could be used in real-time. Process controls and flow cytometic evaluation were highlighted and the effects of cryopreservation were considered. Whole-cell tumor vaccines have been studied intensively and numerous examples were reviewed. Several investigators described their current means of ensuring and documenting lot-to-lot consistency, product characterization and potency. Practical applications of good manufacturing practice (GMP), specific to the tumor vaccine field, were examined. In the discussion of in vitro correlates, a distinction was made between immunologic assessment and immunologic monitoring. The latter, which implies use of a test result to alter clinical therapy, has little place in vaccine trials since none are validated to clinical outcomes. However, immunologic assessment would be of potential value for understanding the biologic effects of the vaccines, including activity and safety. In concert with good laboratory practice (GLP), such tests need to be reproducible, reliable, controlled and provide valid results. Standardization of reagents and procedures across trials was raised as a potential goal for the field. As activities in cell-processing laboratories expand to accommodate new therapeutic needs, regulatory requirements are looming. The members of ISHAGE have already encountered similar issues in preparation of hematopoietic cell transplants and are in a unique position to address the need for methodological consensus and validation. For further information, a transcript of the workshop will be published in the FDA web page and additional information can be obtained from Dr Raj Puri at the FDA. Guidance documents, listed on the ISHAGE web page, can be obtained from the Office of Communication, Training and Manufacturers Assistance at CBER (http://www.fda.gov/ cber/publications.htm).

中文翻译：

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FDA-NCI 肿瘤疫苗研讨会

FDA 和 NCI 于 1998 年 12 月在 NIH 校园共同发起了一个公共研讨会，目的是交流有关肿瘤疫苗特征和疫苗研究临床终点的信息。讨论的问题包括：肿瘤疫苗的监管考虑；树突细胞或其他抗原呈递细胞的表型和功能特征；自体和同种异体肿瘤细胞作为肿瘤疫苗；临床前策略；早期临床试验中的免疫学评估；和检测细胞疫苗中的肿瘤细胞。在监管会议上，FDA 发言人强调，尽管肿瘤疫苗的研究可能具有挑战性，但安全性和有效性仍然至关重要。在准备疫苗试验时，临床前研究应： 提供初始剂量和剂量计划的数据；确定潜在的毒性靶器官；确定用于监测的实验室相关物；并确定疫苗的作用机制。安全问题包括：注射部位反应；诱导自身免疫和淋巴结病；超敏反应；热原性；细胞因子失调; 和诱发疾病。在对试验设计的讨论中，人们认识到对肿瘤疫苗的评估可能会偏离用于癌症化疗的标准方法，特别是考虑到这些药物的急性毒性最小。潜在的替代设计包括： I 期研究，具有大量患者队列，剂量水平和使用最佳生物剂量 (OBD) 之间的间隔较大，而不是最大耐受剂量 (MTD)；具有同期对照的随机 II 期研究，特别是对于生物制剂组合的研究；III 期研究的临床替代终点。然而，实验室相关性不被认为是可接受的终点，特别是对于 III 期研究，除非经验证可预测临床结果。详细回顾了抗原呈递细胞的生物学。涉及的监管方面包括：身份和效力测试；消除污染细胞；功能测定；和抗原表征。要求至少在身份上达成共识，可以实时使用。强调了过程控制和流式细胞术评估，并考虑了冷冻保存的影响。对全细胞肿瘤疫苗进行了深入研究，并审查了许多例子。几位研究人员描述了他们目前确保和记录批次间一致性、产品特性和效力的方法。审查了特定于肿瘤疫苗领域的良好生产规范 (GMP) 的实际应用。在体外相关性的讨论中，区分了免疫评估和免疫监测。后者意味着使用测试结果来改变临床治疗，在疫苗试验中几乎没有地位，因为没有经过临床结果验证。然而，免疫学评估对于了解疫苗的生物学效应（包括活性和安全性）具有潜在价值。与良好实验室规范 (GLP) 相一致，此类测试需要可重复、可靠、可控并提供有效结果。跨试验的试剂和程序标准化被提出作为该领域的潜在目标。随着细胞处理实验室的活动扩大以适应新的治疗需求，监管要求迫在眉睫。ISHAGE 的成员在造血细胞移植的准备过程中已经遇到了类似的问题，并且在解决方法学共识和验证的需求方面处于独特的地位。如需更多信息，研讨会的文字记录将发布在 FDA 网页上，更多信息可从 FDA 的 Raj Puri 博士处获得。可以从 CBER 的通信、培训和制造商援助办公室 (http://www.fda.gov/cber/publications.htm) 获得 ISHAGE 网页上列出的指导文件。随着细胞处理实验室的活动扩大以适应新的治疗需求，监管要求迫在眉睫。ISHAGE 的成员在造血细胞移植的准备过程中已经遇到了类似的问题，并且在解决方法学共识和验证的需求方面处于独特的地位。如需更多信息，研讨会的文字记录将发布在 FDA 网页上，更多信息可从 FDA 的 Raj Puri 博士处获得。可以从 CBER 的通信、培训和制造商援助办公室 (http://www.fda.gov/cber/publications.htm) 获得 ISHAGE 网页上列出的指导文件。随着细胞处理实验室的活动扩大以适应新的治疗需求，监管要求迫在眉睫。ISHAGE 的成员在造血细胞移植的准备过程中已经遇到了类似的问题，并且在解决方法学共识和验证的需求方面处于独特的地位。如需更多信息，研讨会的文字记录将发布在 FDA 网页上，更多信息可从 FDA 的 Raj Puri 博士处获得。可以从 CBER 的通信、培训和制造商援助办公室 (http://www.fda.gov/cber/publications.htm) 获得 ISHAGE 网页上列出的指导文件。ISHAGE 的成员在造血细胞移植的准备过程中已经遇到了类似的问题，并且在解决方法学共识和验证的需求方面处于独特的地位。如需更多信息，研讨会的文字记录将发布在 FDA 网页上，更多信息可从 FDA 的 Raj Puri 博士处获得。可以从 CBER 的通信、培训和制造商援助办公室 (http://www.fda.gov/cber/publications.htm) 获得 ISHAGE 网页上列出的指导文件。ISHAGE 的成员在造血细胞移植的准备过程中已经遇到了类似的问题，并且在解决方法学共识和验证的需求方面处于独特的地位。如需更多信息，研讨会的文字记录将发布在 FDA 网页上，更多信息可从 FDA 的 Raj Puri 博士处获得。可以从 CBER 的通信、培训和制造商援助办公室 (http://www.fda.gov/cber/publications.htm) 获得 ISHAGE 网页上列出的指导文件。研讨会的文字记录将发布在 FDA 网页上，更多信息可从 FDA 的 Raj Puri 博士处获得。可以从 CBER 的通信、培训和制造商援助办公室 (http://www.fda.gov/cber/publications.htm) 获得 ISHAGE 网页上列出的指导文件。研讨会的文字记录将发布在 FDA 网页上，更多信息可从 FDA 的 Raj Puri 博士处获得。可以从 CBER 的通信、培训和制造商援助办公室 (http://www.fda.gov/cber/publications.htm) 获得 ISHAGE 网页上列出的指导文件。